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P66Shc Signaling Mediates Diabetes-Related Cognitive Decline.

ABSTRACT: Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-? accumulation. We investigated the contribution of the p66Shc signaling pathway to diabetes-related cognitive decline using p66Shc knockout (-/-) mice. p66Shc (-/-) mice have less OS in the brain and are resistant to diabetes-induced brain damage. Moreover, p66Shc (-/-) diabetic mice show significantly less cognitive dysfunction and decreased levels of OS and the numbers of microglia. This study postulates a p66Shc-mediated inflammatory cascade leading to OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment that is at least partially mediated through an AD-pathology-independent mechanism.

SUBMITTER: Minami Y

PROVIDER: S-EPMC5816624 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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p66Shc Signaling Mediates Diabetes-Related Cognitive Decline.

Minami Yohei Y Sonoda Noriyuki N Hayashida Eiichi E Makimura Hiroaki H Ide Makoto M Ikeda Noriko N Ohgidani Masahiro M Kato Takahiro A TA Seki Yoshihiro Y Maeda Yasutaka Y Kanba Shigenobu S Takayanagi Ryoichi R Ogawa Yoshihiro Y Inoguchi Toyoshi T

Scientific reports 20180216 1

Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-β accumulation. We investigated the co ...[more]

PMID: 29453337

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Project description:ObjectiveThe goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories.MethodsParticipants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18 F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aβ-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline.ResultsWomen showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). β-amyloid (Aβ)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aβ + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04).InterpretationTau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aβ were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932.

Dataset Information

P66Shc Signaling Mediates Diabetes-Related Cognitive Decline.

Publications

p66Shc Signaling Mediates Diabetes-Related Cognitive Decline.

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